Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C1Cc2ccccc2N1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1Cc2ccccc2N1C(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of indoline-2-carboxilic acid (6.52 g, 40 mmol) and triethyl amine (11 mL, 78 mmol) in anhydrous CH2Cl2 (100 mL) was added dropwise a solution of benzoyl chloride (5.62 g, 40 mmol) in CH2Cl2 (25 mL) at 0° C. The reaction mixture was stirred at this temperature for 15 min and then at room temperature for additional 2.5 hours. The reaction mixture was washed successively with 5% aqueous KHSO4 solution (2×20 mL), brine (25 mL), dried over Na2SO4, and evaporated under reduced pressure to dryness. The residue was chromatographed on a silica gel column (3×35 cm) using CHCl3/MeOH (100:1) as the eluent. The main fractions containing the desired product was combined, evaporated under reduced pressure to dryness and the solid residue was recrystallized from MeOH to give the known 1-benzoyl-2,3-dihydro-1H-indole-2-carboxylic acid, 10.66 g (81%): mp 209-210° C. (191-193° C.)19; 1H NMR (DMSO-d6) δ 3.09 (1H, d, J=16.3 Hz, CH), 3.61-3.63 (1H, m, N—CH), 4.97 (1H, brs, CH), 7.06 (1H, m, ArH), 7.25-7.26 (2H, m, 2×ArH), 7.49 (5H, m, 5×ArH), 8.14-8.17 (1H, m, ArH), 13.01 (1H, brs, exchangeable, OH). MS: m/z 268.0 (M+H)+.
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[C:12]1[N:13]([CH3:31])[C:14](=[O:30])[CH:15]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:17]=1[C:18]([O-:20])=O.[NH2:32][CH2:33][CH2:34][CH2:35][OH:36].CCN(C(C)C)C(C)C>C1COCC1>[F:29][C:23]1[CH:24]=[C:25]([I:28])[CH:26]=[CH:27][C:22]=1[NH:21][C:16]1[C:17]([C:18]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:20])=[CH:12][N:13]([CH3:31])[C:14](=[O:30])[CH:15]=1
Reactant: NCCCO
Reactant: Cn1c(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)[O-])c(Nc2ccc(I)cc2F)cc1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)NCCCO)c(Nc2ccc(I)cc2F)cc1=O
Yield: 95 %

Procedure:
2,3,4,5,6-Pentafluorophenyl-4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with 3-aminopropanol in THF in the presence of DIEA as for example 4, step B. The reaction solvent was removed under reduced pressure and the resulting oil purified by chromatography on silica gel (50% acetone/CH2Cl2) to give 4-(2-fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (95%), m.p. (Et2O) 81-86° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.11 (s, 1H), 8.40 (br s, 1H), 8.24 (s, 1H), 7.74 (d, J=9.7 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H), 5.59 (s, 1H), 4.48 (t, J=5.1 Hz, 1H), 3.48 (q, J=5.7 Hz, 2H), 3.37 (s, 3H), 3.30-3.24 (m, 2H), 1.67 (pentet, J=6.7 Hz, 2H). Anal. Calcd for C16H17FIN3O3.0.5H2O: C, 42.3; H, 4.0; N, 9.3. Found: C, 42.2; H, 3.8; N, 9.1.
Reaction SMILES: [IH:1].[CH3:2][O:3][CH:4]([O:12][CH3:13])[CH2:5][NH:6][C:7](SC)=[N:8][CH3:9].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:27]3[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=3[N:25]=2)[CH2:19][CH2:18]1>CC(O)C>[IH:1].[CH3:2][O:3][CH:4]([O:12][CH3:13])[CH2:5][NH:6][C:7]([NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:27]3[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=3[N:25]=2)[CH2:19][CH2:18]1)=[N:8][CH3:9]
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CN=C(NCC(OC)OC)SC
Agent: I
Solvent: CC(C)O
Product: CN=C(NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)NCC(OC)OC
Yield: 99 %

Procedure:
A mixture of 12.8 parts of methyl N-(2,2-dimethoxyethyl)-N'-methylcarbamimidothioate monohydroiodide, 13.2 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine and 160 parts of 2-propanol was stirred and refluxed overnight. The reaction mixture was evaporated, yielding 23 parts (99%) of N-(2,2-dimethoxyethyl)-N'-[2-[4[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N"-methylguanidine monohydroiodide (195).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>CS(C)=O.[Cu]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(Sc2ccc(C(=O)O)cc2)cc1
Temperature: 210 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A mixture of 6.0 g of 4-mercapto-toluene and 9.2 g of potassium t-butoxide is stirred at room temperature under a nitrogen atmosphere in 50 ml of dimethylsulfoxide for 10 minutes followed by the addition of 11.5 g of 4-bromobenzoic acid and 0.2 g of copper metal. The reaction mixture is stirred at 210° C. for 16 hours. The reaction mixture is poured over crushed ice and filtered through diatomaceous earth. The filtrate is acidified with HCl until pH 2. The resulting solid is collected, washed with water and 60 ml of petroleum ether to give 8.5 g of the desired product, m.p. 105°-107° C., M+H=245.
Reaction SMILES: [CH:1]1([C@H:4]([NH:8]C(=O)[O-])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1.[ClH:12]>CCO.C(Cl)(Cl)Cl.O1CCOCC1.[Pd]>[ClH:12].[CH:1]1([C@H:4]([NH2:8])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1
Reactant: COC[C@@H](NC(=O)[O-])C1CC1
Agent: [Pd]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COC[C@@H](N)C1CC1
Yield: 100 %

Procedure:
To a solution of (S)-1-cyclopropyl-2-methoxyethylcarbamate (4.36 g, 17.5 mmol) in EtOH (80 ml) and CHCl3 (3 mL) in a Parr bottle was added 4 N HCl in dioxane (5 mL) and Pd/C (476 mg, 10%, wet, Degussa type). The mixture was placed on a Parr shaker under H2 atm at 45 psi for 16 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated then reconcentrated from hexanes (2×) to afford (S)-1-cyclopropyl-2-methoxyethanamine hydrochloride (2.65 g, 100% yield) as a white solid: mp 190-192° C.; [α]25D+14.3 (c 0.446, MeOH); 1H NMR (400 MHz, CDCl3) δ 8.41 (s br, 3H), 3.68 (d, J=5.6 Hz, 2H), 3.39 (s, 3H), 2.64-2.60 (m, 1H), 1.20-1.13 (m, 1H), 0.71-0.58 (m, 3H), 0.32-0.28 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 72.1, 59.2, 57.5, 10.7, 4.2, 4.1; LRMS (ESI m/e 231.2 [(2M+H)+, calcd for C12H27N2O2 231.2].
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:19])[CH2:14][O:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1F.CCO>CN(C=O)C.Cl>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[O:19][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][O:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)OC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)OC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-isopropoxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (25.0 mg, 91.4 μmol) was dissolved in DMF (190 μL). NaH (2.6 mg, 109.7 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Dichloro-1-fluorobenzene (21.4 μL, 182.9 μmol) was added and the mixture was stirred at 70° C. for 3 hours. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (949 μL, 1.1 mmol) and stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt oil (29.5 mg, 97% purity). MS m/z: [M+H]+ calcd for C15H21Cl2NO2, 318.10; found 318.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:20][O:19][C:18]([NH2:21])=[N:17]4)[C:4]=2[CH:3]=1)=[CH:14][C:13]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:12][CH:11]=3.F[C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1.N1C=CC=C(B(O)O)C=1>>[F:8][C:6]1[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:20][O:19][C:18]([NH2:21])=[N:17]4)[C:4]=2[CH:3]=[C:2]([C:35]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[N:7]=1)=[CH:14][C:13]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:12][CH:11]=3
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(Cl)nc1F
Agent: OB(O)c1cccnc1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(-c2cccnc2)nc1F

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA1 above, but using (S)-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared as described as in Method BB33), 2-fluoropyridin-3-ylboronic acid and 3-pyridylboronic acid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=N1.N1CCCC[CH2:32]1>CO>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22](/[CH:29]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[CH:32]1
Reactant: COc1ccc2c(c1CN1CCOCC1)OCC2=O
Reactant: O=Cc1n[nH]c2ncccc12
Reactant: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CN1CCOCC1)O/C(=C\c1c[nH]c3ncccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 216.9 %

Procedure:
A solution of 6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.131 g, 0.500 mmol) obtained in Example A41, Step 2 in methanol (1.2 mL) was added with 7-aza-1H-indazole-3-carboxaldehyde (0.0545 g, 0.373 mmol) and piperidine (0.00265 g, 0.0311 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then added with methanol (2 mL), and the precipitated solid was suspended in methanol and thereby washed to obtain the objective (Z)-2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.0264 g, 21%).
Reaction SMILES: C1C[O:4]CC1.[CH2:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([F:25])[C:18]([F:24])=[CH:19][CH:20]=3)[O:15]2)[CH2:10][CH2:9]1)[CH3:7].C([Li])CCC.CCCCCC.OO>O.C(O)(=O)C>[CH2:6]([C@H:8]1[CH2:9][CH2:10][C@H:11]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([F:25])[C:18]([F:24])=[C:19]([OH:4])[CH:20]=3)[O:15]2)[CH2:12][CH2:13]1)[CH3:7]
Reactant: CC[C@H]1CC[C@H](C2CCc3ccc(F)c(F)c3O2)CC1
Reactant: C1CCOC1
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: CC[C@H]1CC[C@H](C2CCc3cc(O)c(F)c(F)c3O2)CC1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
Into the THF (150 ml) solution of 2-(trans-4-ethylcyclohexyl)-7,8-difluorochroman (28 g), a 1.6 M butyllithium-hexane solution (65 ml) was added dropwise at −60° C., and stirred for 2 hours at −50° C. Into this, borate trimethyl (15 g) was added dropwise, stirred for 30 minutes, and warmed to 0° C. over 2 hours. Into this, acetic acid (10 ml) was added, and stirred for 20 minutes, to which 30% hydrogen peroxide aqueous solution (20 ml) was gradually added, and stirred for 1 hour. Into this, water (100 ml) was added, which was subjected to extraction using ethyl acetate, followed by concentration. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2-(trans-4-ethylcyclohexyl)-7,8-difluoro-6-hydroxychroman (28 g).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[CH2:6][N:7]([C:9]([C:11]1[C:20]2[C:15](=[C:16]([S:23][C:24]([F:27])([F:26])[F:25])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[S:10])[CH3:8].O>COCCO>[CH3:22][O:21][C:17]1[C:16]([S:23][C:24]([F:26])([F:25])[F:27])=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([C:9](=[S:10])[N:7]([CH3:8])[CH2:6][C:5]([OH:28])=[O:4])=[CH:12][CH:13]=[CH:14]2
Reactant: COC(=O)CN(C)C(=S)c1cccc2c(SC(F)(F)F)c(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: COc1ccc2c(C(=S)N(C)CC(=O)O)cccc2c1SC(F)(F)F
Reaction time: 4 h
Yield: 50.8 %

Procedure:
Aqueous NaOH (3.41 mL, 2 N) was added to a solution of N-[[6-methoxy-5-(trifluoromethylthio)-1-naphthalenyl]thioxomethyl]-N-methylglycine methyl ester (1.375 g, 3.4 mmoles) in 2-methoxyethanol (20 ml). The solution was stirred at 20°-22° C. for 4 hr. Water was added and the cloudy mixture was extracted with ethyl acetate. The aqueous layer was made acidic (pH=3) with 1 N aqueous HCl and extracted with ethyl acetate. The latter extract was washed successively with water and brine, dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from chloroform-hexane to give the title compound (672 mg); mp 168°-169° C.; NMR (DMSO-d6) δ 3.0 (s, 3H), 4.0 (s, 3H), 4.6 and 5.2 (d, J=16.5 Hz, 2H), 7.7 (m, 5H); ir (white mineral oil) 2900, 1720, 1465 cm-1 ; uvλmax (MeOH) 342 nm (ε4970), 334 (4800), 230 (46,800).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:26]([F:40])([F:41])[C:27]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccc(C(F)(F)F)cc3C(F)(F)F)nncc2c1
Temperature: 120 °C

Procedure:
In a microwave tube was placed 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.097 g, 0.29 mmol), 2,4-bis(trifluoromethyl)benzeneboronic acid (0.074 g, 0.29 mmol), tetrakis(triphenylphosphine)palladium (0) (0.033 g, 0.029 mmol) and 2M potassium carbonate (0.43 mL, 0.86 mmol) in 1.5 mL of DME/EtOH (4/1). The mixture was heated in the microwave at 120° C. for 20 minutes. After cooling, water was added and the mixture was extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by HPLC to give 3-(1-(2,4-bis(trifluoromethyl)phenyl)phthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide as an off-white solid. MS (ES+)=516.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15]Br)[O:8][CH2:7][C:6]2([CH3:18])[CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:31][CH2:30][N:29]([CH2:15][CH:9]3[C:10]4[CH:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[C:6]([CH3:18])([CH3:17])[CH2:7][O:8]3)[CH2:28][CH:27]=2)=[CH:22][CH:21]=1
Reactant: COc1cc2c(cc1OC)C(C)(C)COC2CBr
Reactant: Clc1ccc(C2=CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(C)(C)COC2CN1CC=C(c2ccc(Cl)cc2)CC1
Yield: 21 %

Procedure:
A mixture of 1.52 g of 6,7-dimethoxy-4,4-dimethyl-1-bromomethylisochroman, 1.35 g of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine, and 2 ml. of triethylamine in 5 ml of DMF are heated at 50° C. for 23 hr. The mixture is partitioned between methylene chloride and aqueous potassium carbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed over silica gel utilizing 5% methanol/1/2% ammonium hydroxide/methylene chloride to give a 21% yield 4-(4-chloro phenyl)-1-[(3,4-dihydro-4,4-dimethyl-6,7-dimethoxy-1H-2-benzopyran-1-yl)methyl]-1,2,3,6-tetrahydropyridine.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22].[F:28][C:29]1[CH:30]=[C:31]([CH2:36][C:37](O)=[O:38])[CH:32]=[C:33]([F:35])[CH:34]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[F:28][C:29]1[CH:30]=[C:31]([CH2:36][C:37]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:27])[CH2:23][CH:24]([CH3:25])[CH3:26])=[O:38])[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N1-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-L-leucinamide (64 g) (65 mg, 0.177 mmol) in dichloromethane (2 mL) was added 3,5-difluorophenylacetic acid (35 mg, 0.230 mmol), HOBt (31 mg, 0.230 mmol), NMM (25 mg, 0.248 mmol) and EDAC-HCl (44 mg, 0.230 mmol). The mixture was stirred at ambient temperature under nitrogen overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic extracts were washed in succession with saturated aqueous sodium bicarbonate and 1N aqueous HCl. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 6:1 (v/v) dichloromethane:ethyl acetate to afford the title compound in a 1:1 mixture with the 2S,3R diastereomer (65 mg, 70%) as a white solid. TLC Rf=0.31 (6:1 dichloromethane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ0.82 (m, 6H), 1.21-1.55 (m, 3H), 3.48 (s, 2H), 4.28 (m, 1H), 5.15 (t, 1H, J=7.2 Hz), 5.76 (m, 2H), 6.27 (d, 1H, J=7.0 Hz), 6.78 (m, 3H), 7.06 (m, 1H), 7.15-7.42 (m, 8H), 7.55 (br s, 1H). MS APCI, m/z=510 (M+1). LC/MS: 2.40 min.
Reaction SMILES: [CH:1]([N:4]1[C:12](=[O:13])[NH:11][C:10]2[C:5]1=[N:6][C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)=[N:8][C:9]=2[C:14]([O-:16])=O)([CH3:3])[CH3:2].[NH2:24]C1C(C([O-])=O)=NC(C2C=CC=C(O)C=2)=NC=1NC(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH:1]([N:4]1[C:12](=[O:13])[NH:11][C:10]2[C:5]1=[N:6][C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)=[N:8][C:9]=2[C:14]([NH2:24])=[O:16])([CH3:2])[CH3:3]
Reactant: CC(C)n1c(=O)[nH]c2c(C(=O)[O-])nc(-c3cccc(O)c3)nc21
Reactant: CC(C)Nc1nc(-c2cccc(O)c2)nc(C(=O)[O-])c1N
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)n1c(=O)[nH]c2c(C(N)=O)nc(-c3cccc(O)c3)nc21
Yield: 63 %

Procedure:
9-Isopropyl-2-(3-hydroxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. 5-Amino-6-isopropylamino-2-(3-hydroxy-phenyl)-pyrimidine-4-carboxylate (0.43 g, 1.4 mmol) and 1,1′-carbonyldiimidazole (1.1 g, 6.8 mmol) were reacted according to General Procedure F. The crude residue was triturated with methylene chloride and cold hexanes to afford the title compound as a white solid (0.29 g, 0.85 mmol, 63% yield). MS (ESI) m/z 343.4 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=[O:13].[Br:14]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:14][C:11]1[N:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]([CH:12]=[O:13])=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccn1-c1ncccn1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Br)n1-c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a solution of 0.5 g of 1-(2-pyrimidinyl)-1H-pyrrole-2-carbaldehyde in 10 ml of N,N-dimethylformamide was added 0.6 g of N-bromosuccinimide. The resulting mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.43 g of 5-bromo-1-(2-pyrimidinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:17][C@H:11]2[CH2:12][N:13]([C:15]#[N:16])[CH2:14][C@@:10]2([C:18]([N:20]2[CH2:29][CH2:28][C:27]3[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=3[CH2:21]2)=[O:19])[CH2:9]1)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:7][C@@H:8]1[CH2:17][C@H:11]2[CH2:12][N:13]([C:15]([NH2:16])=[O:36])[CH2:14][C@@:10]2([C:18]([N:20]2[CH2:29][CH2:28][C:27]3[N:26]=[CH:25][C:24]([C:30]([F:31])([F:33])[F:32])=[CH:23][C:22]=3[CH2:21]2)=[O:19])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2CN(C#N)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)N1C[C@@H]2C[C@@H](N)C[C@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1

Procedure:
A solution of the product from Step A (0.19 g, 0.396 mmol) in TFA (1.5 mL) and DCM (1.5 mL) was stirred at rt for 1.5 h. Concentration by rotary evaporation was followed by dilution with DCM and additional evaporation to give the product as a TFA salt. LC/MS: C18H22F3N5O2: m/z 398.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:14]Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:11]([Cl:10])[CH:12]=2)[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(Cl)c1O
Reactant: ClCc1ccc(Cl)c(Cl)c1
Solvent: O
Product: Cc1cc(Cc2ccc(Cl)c(Cl)c2)cc(Cl)c1O
Temperature: 60 °C
Reaction time: 5.5 h

Procedure:
90.4 g (0.63 mol) 2-chloro-6-methylphenol are brought to reaction with 149.4 g (0.765 mol) 3,4-dichlorobenzylchloride and 2.4 g water-free, finely mortared ZnCL2 without solvent. After stirring 5-6 h at 60° C. the reaction mixture is subsequently worked up by washing three times, each with 100 ml water.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:25]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:26]=2[S:27][C:28]=1[CH2:29][CH3:30])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:20][NH:21][C:22]([C:24]1[C:25]2[CH:34]=[CH:33][C:32]([O:35][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:31][C:26]=2[S:27][C:28]=1[CH2:29][CH3:30])=[O:23]
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](OC)C5)sc34)ccc2c1C(=O)NC
Yield: 27.4 %

Procedure:
This material was prepared by reacting 7-chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 4b (74 mg, 0.25 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (71 mg, 0.30 mmole) and Cs2CO3 (244 mg, 0.75 mmole) in a manner analogous to that described for example 1 to give a yellow solid (34 mg, 19%). 1H NMR (DMSO-d6, 300 MHz), δ 8.59 (1H, d, J=5.31 Hz), 8.33 (1H, q, J=4.46 Hz), 8.06 (1H, s), 7.99 (1H, d, J=2.27 Hz), 7.81 (1H, d, J=8.84 Hz), 7.34 (1H, dd, J=2.27, 8.84 Hz), 6.76 (1H, d, J=5.56 Hz), 4.08–3.83 (3H, m), 3.67–3.48 (2H, m), 3.27, 3.24 (3H, s), 3.00 (2H, t, J=7.49 Hz), 2.83 (3H, d, J=4.55 Hz), 2.16–1.95 (2H, m), 1.28 (3H, t, J=7.58 Hz).